Warning(s)

Extended-release Hydrocodone Bitartrate

Risk of addiction, abuse, and misuse, which can lead to overdose and death, in patients and other users.122 Assess each patient’s risk for addiction, abuse, and misuse before prescribing the drug; monitor all patients regularly for development of these behaviors or conditions.122 (See Addiction, Abuse, and Misuse under Cautions.)

Serious, life-threatening, or fatal respiratory depression may occur.122 Monitor for respiratory depression, especially during initiation of therapy and following any dosage increase.122 (See Respiratory Depression under Cautions.)

Patients must swallow extended-release capsules whole; crushing, chewing, or dissolving the capsules can cause rapid release of the drug and absorption of a potentially fatal dose.122

Accidental ingestion of even 1 dose, especially by a child, can result in a fatal overdose.122

Prolonged maternal use of opiates during pregnancy can result in neonatal withdrawal syndrome, which may be life-threatening.122 (See Pregnancy under Cautions.)

Patients must not consume alcoholic beverages or take prescription or nonprescription preparations containing alcohol; use of alcohol with the extended-release capsules may result in increased plasma concentrations of hydrocodone and a potentially fatal overdose.122

REMS:

FDA approved a REMS for hydrocodone to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of hydrocodone and consists of the following: medication guide and elements to assure safe use. See the FDA REMS page () or the ASHP REMS Resource Center (). (Also see Risk Evaluation and Mitigation Strategy under Dosage and Administration.)

Introduction

Uses for Hydrocodone Bitartrate

Pain

Extended-release hydrocodone: Relief of pain that is severe enough to require long-term, daily, around-the-clock use of an opiate analgesic and for which alternative treatment options (e.g., nonopiate analgesics or immediate-release opiates) are inadequate or not tolerated.122Not indicated for as-needed (“prn”) use.122

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Hydrocodone/ibuprofen fixed combinations: Short-term (generally <10 days) use for the relief of acute pain; not indicated for management of pain associated with such chronic conditions as osteoarthritis or rheumatoid arthritis.124

Combinations of hydrocodone and NSAIAs or acetaminophen may produce additive analgesic effects because of differing mechanisms of action.c

Cough

Symptomatic relief of nonproductive cough, alone or in combination with other antitussives or expectorants.b

Hydrocodone Bitartrate Dosage and Administration

General

Risk Evaluation and Mitigation Strategy

FDA has approved a REMS for hydrocodone extended-release capsules.125 (See REMS.) The REMS consists of a medication guide that must be dispensed with every prescription for the extended-release capsules and training materials that must be made available to clinicians who prescribe the extended-release preparation.125 The goal is to inform patients and clinicians about the potential for overdosage, misuse and abuse, and addiction to the drug and to ensure safe use of the drug.125

Administration

Oral Administration

Hydrocodone Extended-release Capsules

Must be swallowed whole, one capsule at a time, with enough water to ensure complete swallowing of the capsule immediately after it is placed in the mouth.122

Crushing, chewing, or dissolving the capsules will result in uncontrolled delivery of hydrocodone and can result in overdosage and death.122

Patients must not consume alcoholic beverages or take prescription or nonprescription preparations containing alcohol during therapy; concomitant ingestion of alcohol may result in increased plasma concentrations of the drug and a potentially fatal overdose.122

Use a calibrated dosing device when measuring doses of the suspension.109112 Use of a household teaspoon could result in overdosage, especially when pediatric doses (2.5 mL of suspension) are measured.109112

Do not give more frequently than every 12 hours; if cough is not controlled, contact clinician.112

Do not dilute with fluids or mix with other drugs; shake well prior to administration.109

Dosage

Available as hydrocodone bitartrate and hydrocodone polistirex; dosage expressed in terms of hydrocodone bitartrate.abc109

Pain (Hydrocodone Bitartrate Extended-release Capsules [Zohydro ER])

Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression.122 (See Respiratory Depression under Cautions.) Individualize initial dosage based on patient's prior analgesic use and risk factors for addiction, abuse, and misuse.122

Use single doses >40 mg, the 50-mg extended-release capsules, and total daily dosages >80 mg only in patients in whom tolerance to an opiate of comparable potency has been established.122

Patients are considered opiate tolerant if they have been receiving at least 60 mg of oral morphine sulfate daily, 25 mcg of transdermal fentanyl per hour, 30 mg of oral oxycodone hydrochloride daily, 8 mg of oral hydromorphone hydrochloride daily, 25 mg of oral oxymorphone hydrochloride daily, or an equianalgesic dose of another opiate daily for at least 1 week.122

Initiation of Extended-release Hydrocodone Therapy in Opiate-naive or Nontolerant Patients

Oral

Initially, 10 mg every 12 hours.122 Higher initial dosages in patients who are not opiate tolerant may result in fatal respiratory depression.122

Initial Dosage Selection in Patients Being Switched from Other Chronic Oral Opiate Therapy to Extended-release Hydrocodone

Oral

Discontinue all other around-the-clock opiates when therapy with extended-release hydrocodone is initiated.122

Carefully individualize dosage; overestimation of initial dosage in opiate-tolerant patients can result in fatal overdosage.122

Use conversion factors in Table 1 as a guide for selecting initial extended-release hydrocodone dosage for patients being transferred from therapy with an oral opiate listed in the table.122 The doses in Table 1 are not equianalgesic, and the table cannot be used to transfer patients from extended-release hydrocodone to another opiate, as this will overestimate the dosage and may result in fatal overdosage.122

For patients receiving a single opiate analgesic, multiply the current total daily dosage of the opiate by the conversion factor to calculate the approximate daily dosage of extended-release hydrocodone; divide the calculated daily dosage in half for administration every 12 hours.122

For patients receiving >1 opiate analgesic, calculate the approximate daily dosage of extended-release hydrocodone for each opiate and then add those totals to obtain the approximate total daily dosage of extended-release hydrocodone; divide the calculated total daily dosage in half for administration every 12 hours.122

For patients receiving analgesics containing opiates and nonopiates in a fixed ratio, consider only the opiate component in the conversion.122

If calculated doses do not correspond to an available tablet strength, always round dosage down to the nearest whole capsule.122

Monitor for opiate withdrawal and for oversedation or toxicity following transfer to extended-release hydrocodone.122

Particularly close monitoring required following switch from methadone, since conversion ratios between methadone and other opiates vary widely depending on extent of prior methadone exposure and because methadone has a long half-life and tends to accumulate in plasma.122

Initial Dosage Selection in Patients Being Switched from Transdermal Fentanyl to Extended-release Hydrocodone

Oral

Wait 18 hours after removal of the transdermal fentanyl system to initiate therapy with extended-release hydrocodone; use an initial conservative dosage of approximately 10 mg every 12 hours for each 25 mcg/hr of transdermal fentanyl.122

Monitor closely; experience with this dosage conversion is limited.122

Dosage Adjustment to Achieve Adequate Analgesia

Oral

Adjust dosage gradually, every 3–7 days in increments of 10 mg every 12 hours, to provide adequate analgesia and to minimize adverse effects.122

Discontinuance of Therapy

Oral

Gradually taper dosage every 2–4 days to avoid manifestations of abrupt withdrawal.122

Pain (Immediate-release Fixed Combinations)

Oral

2.5–10 mg (in fixed combination with ibuprofen) every 4–6 hours as needed, generally for <10 days.124132 Manufacturers state total daily dosage should not exceed 5 tablets (each providing from 2.5–10 mg of hydrocodone bitartrate and 200 mg of ibuprofen).124132

Adjust dosage according to severity of pain and response and tolerance of the patient.123124a

Nonopiate-containing analgesic fixed combinations: Nonopiate component may limit dosage of opiate component.117119120121 Nonopiate analgesics are available in various fixed ratios with hydrocodone and also are available in many other prescription and OTC preparations; ensure that therapy is not duplicated and that nonopiate dosage does not exceed maximum recommended dosages.117118119121

Warnings/Precautions

Warnings

Respiratory Depression

Even therapeutic doses of hydrocodone may decrease respiratory drive to the point of apnea in patients with COPD, cor pulmonale, substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression.122 Monitor closely, particularly when initiating therapy or titrating dosage.122 Use nonopiate analgesics if possible.122

Geriatric, cachectic, and debilitated patients are at increased risk of life-threatening respiratory depression.122 Close monitoring of therapy with extended-release hydrocodone is required, particularly following initiation of therapy, during dosage titration, and during concomitant therapy with other respiratory depressants.122

Serious, life-threatening, or fatal respiratory depression reported with use of modified-release (e.g., extended-release) opiates, even when used as recommended; can occur at any time during therapy, but risk is greatest during initiation of therapy and following dosage increases.122 Monitor for respiratory depression, especially during the first 24–72 hours of therapy and following any dosage increase.122

Only clinicians who are knowledgeable in the use of potent opiates for the management of chronic pain should prescribe extended-release hydrocodone.122

Appropriate dosage selection and titration of extended-release hydrocodone are essential to reduce the risk of respiratory depression; overestimation of the dosage when transferring patients from another opiate can result in fatal overdosage with the first dose.122

Accidental ingestion of even 1 dose of extended-release hydrocodone, especially by a child, can result in respiratory depression and a fatal overdose.122

Potential for increased viscosity of bronchial secretions and suppression of cough reflex, with subsequent respiratory insufficiency, in patients with asthma or pulmonary emphysema who indiscriminately use antitussives.b

Addiction, Abuse, and Misuse

Addiction can occur with appropriately prescribed or illicitly obtained opiates, and at recommended dosages or with misuse or abuse.122

Assess each patient’s risk for addiction, abuse, and misuse prior to prescribing; monitor all patients for development of these behaviors or conditions.122 Personal or family history of substance abuse (drug or alcohol addiction or abuse) or mental illness (e.g., major depression) increases risk.122

The potential for addiction, abuse, and misuse should not prevent opiate prescribing for appropriate pain management, but does necessitate intensive counseling about risks and proper use and intensive monitoring for these behaviors and conditions.122

Modified-release (e.g., extended-release) opiates are associated with a greater risk of overdose and death because of the larger amount of drug contained in each dosage unit.122

Abuse or misuse of extended-release hydrocodone (Zohydro ER) by crushing or chewing the capsules, snorting the capsule contents, or injecting the dissolved capsule contents will result in uncontrolled delivery of hydrocodone and can result in a fatal overdose.122

Because of the challenges associated with providing access to an adequate array of options for management of chronic pain while simultaneously preventing prescription opiate abuse and misuse, FDA's decision to approve hydrocodone bitartrate extended-release capsules (Zohydro ER) was controversial, as the formulation lacks tamper-resistant features that might deter abuse and, like other extended-release opiates, some strengths contain substantial amounts of the drug.126127128129130

Potential for abuse of hydrocodone-containing combinations is similar to that of schedule II (C-II) oxycodone-containing combinations.290291 Because of increasing concerns about misuse, abuse, and diversion, hydrocodone-containing fixed-combination analgesic and antitussive preparations previously subject to control as C-III drugs were rescheduled as C-II drugs effective October 6, 2014.290291 (See Preparations.)

Other Warnings/Precautions

Shares the toxic potentials of the opiate agonists; observe the usual precautions of opiate agonist therapy.a

CNS Depression

Performance of activities requiring mental alertness and physical coordination may be impaired.bce109122123124

Concurrent use of other CNS depressants may potentiate CNS depression.be109123124 Concurrent use of other CNS depressants with extended-release hydrocodone may result in profound CNS depression.122 (See Specific Drugs under Interactions.)

When considering the use of extended-release hydrocodone in a patient receiving a CNS depressant, assess duration of use of the CNS depressant; patient’s response, including degree of tolerance to CNS depression; and patient’s use of alcohol or illicit drugs that cause CNS depression.122

Increased Intracranial Pressure or Head Trauma

Respiratory depressant effects and ability of opiates to increase CSF pressure may be markedly exaggerated in patients with head injury, other intracranial lesions, or preexisting elevation in intracranial pressure.bce109122123124

Hydrocodone produces effects (e.g., pupillary changes, altered consciousness) that may obscure clinical course and neurologic signs of further increase in CSF pressure in patients with head injuries.bce109122123124

Closely monitor patients with increased intracranial pressure or impaired consciousness.122 Avoid use of extended-release hydrocodone in patients with impaired consciousness or coma.122

May cause severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients.122

Avoid use of extended-release hydrocodone in patients with circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and BP.122

Acute Abdominal Conditions

May obscure diagnosis or clinical course of patients with acute abdominal conditions.e109122123124

Obstructive Bowel Disease

May diminish propulsive peristaltic waves in GI tract and decrease bowel motility.122 Use may result in obstructive bowel disease, especially in patients with underlying intestinal motility disorder.109

Interactions with Drugs that Affect CYP3A4

Concomitant use of CYP3A4 inducers may result in decreased plasma hydrocodone concentrations, lack of efficacy, or manifestations of withdrawal.122 (See Drugs Affecting Hepatic Microsomal Enzymes under Interactions.)

Fixed-Combination Preparations

When used in fixed combination with other drugs, consider the cautions, precautions, and contraindications associated with the other drug(s).a123124

Specific Populations

Pregnancy

Prolonged maternal use of opiates during pregnancy can result in neonatal opiate withdrawal syndrome; in contrast to adults, withdrawal syndrome in neonates may be life-threatening and requires management according to protocols developed by neonatology experts.122 Syndrome presents with irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.122

Lactation

Low concentrations of hydrocodone and metabolite (hydromorphone) reported in breast milk of women receiving hydrocodone for postpartum pain.122 Discontinue nursing or the drug.109123124

Pediatric Use

Safety and efficacy as an analgesic not established in pediatric patients.122123124

Extended-release oral suspension containing hydrocodone polistirex and chlorpheniramine polistirex: Contraindicated in children <6 years of age; use with caution in children ≥6 years of age due to the risk of respiratory depression.109112 Risk of potentially fatal respiratory depression is increased with overdosage or concomitant use of other respiratory depressants.109 (See Warnings/Precautions and see Dosage and Administration.)

Benefit-to-risk ratio should be carefully considered, especially in children with respiratory embarrassment (e.g., croup).109

Risk of overdosage and toxicity (including death) in children <2 years of age receiving preparations containing antihistamines, cough suppressants, expectorants, and nasal decongestants alone or in combination for relief of symptoms of upper respiratory tract infection.110111 Clinicians should ask caregivers about use of OTC cough/cold preparations to avoid overdosage.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.109122123

May cause confusion and oversedation in geriatric patients.122123 Increased risk of life-threatening respiratory depression in geriatric, cachectic, or debilitated patients.122124

Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in geriatric patients, use with caution and select dosage at the lower end of the dosage range.109122123124

Monitor closely for adverse effects, especially during initiation of therapy and dosage titration and when used concomitantly with other respiratory depressants.122

Hepatic Impairment

Exposure to the drug and the risk of adverse effects may be increased.122 Monitor closely.122 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Exposure to the drug and the risk of adverse effects may be increased.122 Monitor closely.122 (See Renal Impairment under Dosage and Administration.)

Interactions for Hydrocodone Bitartrate

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Possible decreased clearance and increased plasma concentrations of hydrocodone; may result in increased or prolonged opiate effects.122 If concomitant use is necessary, monitor for respiratory depression and sedation at frequent intervals; consider dosage adjustments until stable drug effects are achieved.122

CYP3A4 inducers: Possible increased clearance and decreased plasma concentrations of hydrocodone; may result in lack of efficacy or withdrawal manifestations.122 If concomitant use is necessary, monitor for opiate withdrawal; consider dosage adjustments until stable drug effects are achieved.122

Specific Drugs

Drug

Interaction

Comments

Anticholinergic agents

Possible increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileuse109122124

Hydrocodone Bitartrate Pharmacokinetics

Absorption

Bioavailability

When administered at similar daily dosages, extended-release capsules and immediate-release preparations produce similar overall systemic exposure to hydrocodone, but peak plasma concentrations are lower with the extended-release formulation.122

Extended-release capsules: Peak serum concentrations occur 5 hours after administration.122 AUC and peak concentration are approximately twofold higher on day 7 than on day 1 of therapy.122 At doses up to 50 mg, pharmacokinetics are independent of dose.122

Plasma Protein Binding

Structural similarities to related opiates suggest binding to plasma proteins is not extensive.122124

Elimination

Metabolism

Metabolized by N-demethylation, O-demethylation, and 6-keto reduction to the corresponding 6-α-and 6-β-hydroxy metabolites.122123124 Metabolized principally by CYP3A4 to norhydrocodone (N-demethylation) and to lesser extent by CYP2D6 to hydromorphone (O-demethylation); an unknown low-affinity CYP isoenzyme also may contribute to O-demethylation.122124 Hydromorphone may contribute to hydrocodone's analgesic effects.122124

Opiate agonists act at specific receptor binding sites in the CNS and other tissues; opiate receptors are concentrated in the limbic system, thalamus, striatum, hypothalamus, midbrain, and spinal cord.c

Agonist activity at the opiate μ- or κ-receptor can result in analgesia, miosis, and/or decreased body temperature.c

Agonist activity at the μ-receptor can also result in suppression of opiate withdrawal (and antagonist activity can result in precipitation of withdrawal).c

Respiratory depression may be mediated by μ-receptors, possibly μ2-receptors (which may be distinct from μ1-receptors involved in analgesia); κ- and δ-receptors may also be involved in respiratory depression.c

Suppresses cough reflex by direct effect on cough center in medulla of brain.b109122

Potential for drug to impair mental alertness or physical coordination; avoid driving or operating machinery until effects on individual are known.bce109122123124

Importance of informing clinician if pain control is inadequate or adverse effects (e.g., constipation) occur, so that therapy may be adjusted based on individual requirements.122

Importance of informing patients that hydrocodone is a drug of potential abuse and should be protected from theft or misuse.122124 Importance of properly disposing of the drug when no longer needed.122

Importance of not abruptly discontinuing hydrocodone following prolonged opiate therapy.122

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and alcohol consumption.122123124e Importance of avoiding alcohol-containing beverages or products.122123124

Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.e109122123124 Importance of informing women that chronic use during pregnancy may result in neonatal opiate withdrawal syndrome, which can be life-threatening.122

Importance of advising patients of other important precautionary information.e109122123124 (See Cautions.)

Importance of ensuring that the correct amount of medication required for the intended dose is administered (e.g., importance of using a calibrated dosing device).109

Hydrocodone Bitartrate Extended-release Capsules

Medication guide must be dispensed with each prescription.125 Importance of patients reading the medication guide before initiating therapy and each time the extended-release capsules are dispensed.125

Respiratory depression is most likely to occur following initiation of therapy or an increase in dosage; may occur at recommended dosages of the extended-release capsules.122

Extended-release hydrocodone, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdosage or death.122

Accidental ingestion of extended-release hydrocodone, especially by a child, may result in respiratory depression or death.122 Keep out of reach of children and do not share the drug with others.122

Importance of swallowing capsules whole, one at a time, with enough water to ensure complete swallowing of the capsule immediately after it is placed in the mouth.122 Crushing, chewing, or dissolving the capsules can result in overdosage and death.122

Importance of not consuming alcoholic beverages or taking prescription or nonprescription preparations that contain alcohol; potential for increased hydrocodone absorption from the extended-release capsules and fatal overdosage.122 Do not use other CNS depressants concomitantly unless use is supervised by clinician.122

Risk of orthostatic hypotension and syncope.122 Importance of rising slowly from a seated or supine position and of sitting or lying down if symptoms occur.122

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Single-entity hydrocodone preparations: Subject to control under the Federal Controlled Substances Act of 1970 as schedule II (C-II) drug.

Fixed-combination preparations containing hydrocodone in a concentration of ≤15 mg per dosage unit or 5 mL combined with a therapeutic amount of one or more non-opiate drugs or with a fourfold or greater quantity of isoquinolone opium alkaloid: Previously subject to control as schedule III (C-III) drug; however, rescheduled as C-II drug effective October 6, 2014.290 (See Addiction, Abuse, and Misuse under Cautions.)

Preparations containing hydrocodone in combination with >325 mg of acetaminophen per dosage unit have been discontinued to minimize the risk of inadvertent acetaminophen overdosage; some of these preparations may have been reformulated to limit the amount of acetaminophen to ≤325 mg per dosage unit.288289

Hydrocodone Bitartrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, extended-release

10 mg

Zohydro ER (C-II)

Zogenix

15 mg

Zohydro ER (C-II)

Zogenix

20 mg

Zohydro ER (C-II)

Zogenix

30 mg

Zohydro ER (C-II)

Zogenix

40 mg

Zohydro ER (C-II)

Zogenix

50 mg

Zohydro ER (C-II)

Zogenix

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2015. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

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